EURURO Vol. 72 No. 2

201 320

Platinum Priority – Editorial
Referring to the article published on pp. 192–200 of this issue
Investigating Genomic Aberrations of the Androgen Receptor:
Moving Closer to More Precise Prostate Cancer Care?
Joaquin Mateo, Adam Sharp, Johann S. de Bono [3_TD$DIFF]
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK
In this issue of European Urology, De Laere and colleagues
report on a study profiling the androgen receptor (AR) in
patients with metastatic castration-resistant prostate
cancer (mCRPC), evaluating blood-based assays to analyze
serial tumor mRNA and DNA from circulating tumor cells
(CTCs) and cell-free DNA (cfDNA). In their study, AR
aberrations including point mutations, copy number gains,
structural variations, and alternatively spliced forms of AR
were frequent among mCRPC patients, particularly after
exposure to abiraterone[4_TD$DIFF] and enzalutamide; these events
were detectable from plasma samples. This study builds on
published data on AR genomic aberrations and endocrine
therapy resistance.
Persistent AR signaling despite androgen deprivation
therapy (ADT) is an established feature of mCRPC; further
targeting of this pathway results in tumor responses, as
shown with the successful development of abiraterone
acetate and enzalutamide. Yet, not all patients respond to
these drugs, with response duration being limited and
resistance invariably emerging. A number of studies have
associated primary or secondary resistance to abiraterone
and enzalutamide with specific AR aberrations that result in
continued, and ligand-independent, AR transcriptional
activity ).
Henzler et al recently found AR structural genomic
rearrangements in up to one-third of mCRPC tumor tissue
samples, identifying intrapatient and interpatient hetero-
geneity, with subclonal enrichment for some of these
events. It has been reported that these AR structural
rearrangements generate AR splice variants; these are
constitutively active despite the absence of androgenic
steroid ligands through retention of the AR N-terminus
(AR-NTD) and associated activation function-1 (AF-1)
essential for hormone-independent AR transactivation
and loss of the regulatory carboxy-terminal ligand-binding
domain (LBD). It has been reported that these AR splice
variants are a key mechanism of resistance to androgen
deprivation therapy.
Previous studies using cfDNA to detect copy-number
changes and hotspot mutations associated the emergence of
AR genomic aberrations with resistance to abiraterone and
enzalutamide . Similarly, detection of AR splice variants
in CTCs has been related to poor response to endocrine
therapy, but not taxanes, and survival . While most of
these studies have focused on AR splice variant 7 (AR-V7),
which may not be generated by AR structural rearrange-
ments, several studies show that there are many different
AR splice variants and some of these result in constitutively
active forms that are detectable in CRPC samples.
The use of blood-based assays in this study is clinically
important; if AR genomic aberrations arise after the start of
endocrine therapy, there is a need for assays that are
repeatable and preferably noninvasive. cfDNA may also
allow evaluation of intrapatient heterogeneity of clonal
evolution. It is also important to recognize that these
biomarker studies were largely carried out retrospectively,
utilizing different analytical assays in heterogeneous and
relatively small patient cohorts , so prospective
validation trials are now needed, particularly since the
presence of these biomarkers with resistance to abiraterone
and enzalutamide does not always associate with treatment
resistance, perhaps because of intrapatient heterogeneity
. Emerging data from preclinical studies also report
ava ilable at
journal homepage:
DOI of original article: .
* Corresponding author. Division of Clinical Studies, The Institute of Cancer Research, Drug Development Unit, The Royal Marsden NHS Foundation
Trust, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel. +44 208 7224028; fax: +44 208 6427979.
E-mail address: (J.S. de Bono).
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.